De Novo Synthesis of Possible Candidates for the Inagami–Tamura Endogenous Digitalis-like Factor

De novo synthesis of possible candidates for the Inagami–Tamura endogenous digitalis-like factor (EDLF) was achieved to validate a previously proposed structure. Our synthetic approach involves a highly regio- and diastereoselective Mizoroki–Heck reaction and a Friedel–Crafts-type cyclodehydration to construct steroidal tetracycle 14 as a versatile common intermediate leading to seven 2,14β-dihydroxyestradiol analogues 1a–c, 2a–c, and 3 as possible candidates. By comparing the potency of inhibitory activity against Na+/K+-ATPase between the synthesized candidates and the EDLF, it was found that the proposed structure is not likely to be a true structure of the Inagami–Tamura EDLF.为验证此前提出的结构，我们成功实现了稻永-田村内源性洋地黄样因子（EDLF）潜在候选物的从头合成。本合成策略采用兼具高区域选择性与非对映选择性的沟吕木-赫克（Mizoroki–Heck）反应以及傅-克（Friedel–Crafts）型环脱水反应，构建得到甾体四环骨架14作为通用关键中间体，进而得到7种潜在候选的2,14β-二羟基雌二醇类似物1a–c、2a–c及3。通过对比合成候选物与EDLF对钠钾-ATP酶（Na+/K+-ATPase）的抑制活性强度，我们发现此前提出的结构并非稻永-田村EDLF的真实结构。